To overcome antimalarial drug resistance,carbohydrate derivatives as selective PfHT1 inhibitor have been suggested in recent experimental work with orthosteric and allosteric dual binding pockets.Inspired by this prom...To overcome antimalarial drug resistance,carbohydrate derivatives as selective PfHT1 inhibitor have been suggested in recent experimental work with orthosteric and allosteric dual binding pockets.Inspired by this promising therapeutic strategy,herein,molecular dynamics simulations are performed to investigate the molecular determinants of co-administra-tion on orthosteric and allosteric inhibitors targeting PfHT1.Our binding free energy analyses capture the essential trend of inhibitor binding affinity to protein from published experimental IC50 data in three sets of distinct characteristics.We rank the contribution of key residues as binding sites which categorized into three groups based on linker length,size of tail group,and sugar moiety of inhibitors.The pivotal roles of these key residues are further validated by mutant analysis where mutated to nonpolar alanine leading to reduced affinities to different degrees.The exception was fructose derivative,which exhibited a significant enhanced affinity to mutation on orthosteric sites due to strong changed binding poses.This study may provide useful information for optimized design of precision medicine to circumvent drug-resistant Plasmodium parasites with high efficacy.展开更多
基金supported by the Fundamental Research Funds for the Central Universities(Grant No.3002000-842364006)Beijing-Changping Innovation Joint Fund Project(Grant No.L234003)of Beijing Natural Science Foundation,the Key R&D Program of Shandong Province(Grant No.2023CXPT101)Zhoushan Oceanthink Marine Science&Technology Co.,Ltd.(Grant No.3002000-961236054100)。
文摘To overcome antimalarial drug resistance,carbohydrate derivatives as selective PfHT1 inhibitor have been suggested in recent experimental work with orthosteric and allosteric dual binding pockets.Inspired by this promising therapeutic strategy,herein,molecular dynamics simulations are performed to investigate the molecular determinants of co-administra-tion on orthosteric and allosteric inhibitors targeting PfHT1.Our binding free energy analyses capture the essential trend of inhibitor binding affinity to protein from published experimental IC50 data in three sets of distinct characteristics.We rank the contribution of key residues as binding sites which categorized into three groups based on linker length,size of tail group,and sugar moiety of inhibitors.The pivotal roles of these key residues are further validated by mutant analysis where mutated to nonpolar alanine leading to reduced affinities to different degrees.The exception was fructose derivative,which exhibited a significant enhanced affinity to mutation on orthosteric sites due to strong changed binding poses.This study may provide useful information for optimized design of precision medicine to circumvent drug-resistant Plasmodium parasites with high efficacy.
